Brain Metastases and Available Treatments

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Brain Tumors versus Brain Metastases

Differing between these two types of brain lesions is a common source of confusion for many people. Primary brain tumors are tumors that start in the brain, and are actually quite rare, with an estimated 22,020 new cases in 2010. Brain metastases, commonly called "brain mets" are far more common, and are tumors that have traveled to the brain from another area of the body. It is estimated that between 100,000-170,000 patients develop brain metastases each year.

Let's use an example to better understand this latter concept: a lung cancer is first formed in the lung tissue, but tumor cells can break off from the original mass and travel through the bloodstream or lymph system to other areas of the body, including the brain. This spreading of the tumor is known as "metastasis". When a lung cancer metastasizes to the brain, this "brain tumor" is actually lung cancer cells.

It sounds odd, but if the pathologist took a biopsy of the brain lesion and looked at it under a microscope, it would look like lung cancer cells. It is important to understand the difference between primary brain tumors and brain metastases because they are treated differently. I occasionally hear the media refer to a person who died of lung cancer and brain cancer, when, in actuality, it was lung cancer that had metastasized to the brain.

Among tumor types, lung cancers account for the highest number of brain metastases, with 25% of patients being affected at some time in their disease. Other cancers that commonly metastasize to the brain include melanoma, breast cancer, colon cancer, and renal cell (kidney) cancer. Although these are the most likely types to do so, technically any type of cancer could spread to the brain.

All Tumors Are Not Created Equal

One thing to keep in mind is that all cancers are not equal. Some are more aggressive and/or less susceptible to our treatments than others, and for this reason, prognoses vary greatly from tumor to tumor and person to person. These variations are also important to consider when choosing treatments. For instance, primary lung cancers are quite sensitive to radiation, but melanomas are not. This susceptibility to radiation, or radiosensitivity, does not change once the tumor spreads to the brain. In turn, treatment decisions vary based on the primary (original site) tumor type. However, when it comes to chemotherapy, researchers have known for years that many of the chemotherapy agents commonly used are not able to cross the blood-brain barrier, meaning that the drugs are not able to penetrate the brain, and therefore cannot effectively kill cancer cells that make their way to this sanctuary. Because of this, most chemotherapy agents, generally speaking, are not very effective at treating brain mets, even if they are working well elsewhere in the body; exceptions to this are listed later. For most patients, treatment of brain metastases centers around surgical and radiation techniques. We will review the various treatments available and the relevant supporting data.

Brain Metastases on the Rise

The oncology community has seen a rise in the number of brain metastases in recent years. This may be due to better diagnosis of brain metastases using advanced imaging and also because people are living longer with metastatic disease due to advances in systemic therapy. Unfortunately, in most cancers, once a person develops brain metastases, the tumor is not curable. With current treatments, patients can live from months to years, depending on the number of brain metastases, the type of tumor, and the amount of cancer present in the rest of the body. There are exceptions to this rule in the case of tumors that are highly sensitive to chemotherapy, such as germ cell tumors (testicular), lymphomas, leukemias, and the rare case here and there in other cancer types.

Classifying Brain Metastases

The Radiation Therapy Oncology Group (RTOG) found that certain factors clearly affected the survival of patients and developed a classification system to better evaluate outcomes and help in making treatment decisions. This classification is called recursive partitioning analysis (RPA). The groups are broken down as follows:

Class I : Karnofsky performance status** > 70 (meaning can do normal activity with effort; some signs or symptoms of disease, or better), age < 65, controlled primary tumor, no other metastases

**(Karnofsky performance status is a measure of how well a patient functions. It is commonly used by physicians to classify impairment of function. It rates patients from 0 to 100, with 100 being no complaints with normal functioning and 0 being deceased).

The RTOG found that patients in class I had a median survival of 7.1 months (median is the point at which half of the patients have died and half are still alive); class II had a median survival of 4.2 months; and class III had a median survival of 2.3 months. More analysis has revealed that class II patients that have controlled primary disease have a survival similar to class I patients. These class groupings allow researchers to better determine which patients will benefit from certain treatments.

Treatment Options

Initial Treatment

The danger of brain metastases is the space they take up in the brain and the pressure they put on surrounding tissue. This pressure can cause the symptoms associated with brain lesions, such as headaches, speech difficulties, seizures, nausea/vomiting, weakness of a limb, or visual disturbances. The goal of initial therapy is to relieve some of this pressure on the brain tissue by decreasing swelling using drugs called corticosteroids (dexamethasone, hydrocortisone), either orally or through an intravenous (IV) line. Some patients may see relief of symptoms after starting steroids, but this does not mean the tumor is gone, and so they will still require additional treatment. Some patients will also be given an anti-seizure medication, typically to help prevent further seizures in those who have already experienced one or more seizure events. These medications will help to stabilize the patient until further treatment can be planned.

Whole Brain Radiation Therapy

Whole brain radiotherapy (WBRT) is just what it sounds like – giving radiation to the entire brain. This is generally given in 10 to 15 doses (also called fractions), and is often used in patients with poor prognostic factors (RPA classes II & III), patients who are not candidates for surgery, or patients with more than 3 brain lesions. Many patients may receive WBRT in combination with another therapy (surgery, radiosurgery). You may wonder why one would want to treat the whole brain, when only a small portion contains tumor. The thinking is that there may well be cancer cells in the normal-appearing brain, but just not enough of them yet to form a mass and get "picked up" by radiology studies, so we want to go ahead and attempt to kill them all.

WBRT has been reported to improve symptoms of brain metastases in 70-90% of patients, although some of this benefit is also a result of the corticosteroids. Despite this symptom improvement, recurrence is common, and control of brain metastases is probably only achieved in half of the patients. Patients with tumors that are more sensitive to the effects of radiation fare better (lung and breast, for example) than those with relatively radioresistant tumors (melanoma and renal cancers). It has been difficult to evaluate the long-term effects of WBRT, given the small numbers of patients that survive long-term. These effects could possibly include dementia and a decline in performance status. Studies are looking at combining WBRT with the other therapies, which will be discussed further.

Stereotactic Radiosurgery (SRS)

Stereotatic radiosurgery (SRS) is a confusing term. It is actually not surgery at all, but highly precise administration of a large dose of radiation to the tumor site. Unlike traditional external beam radiation, which is usually given daily over many weeks, SRS is administered in a single dose (Gamma Knife) or up to five doses (Cyberknife® and other linear accelerator-based treatments). More than one brain tumor can be treated during one session (for example, if a patient had 2 separate brain metastases, both could be treated on the same day). Treatments are administered by a traditional radiation machine called a linear accelerator or a specialized machine (including Gamma Knife®). XKnife™ and BrainLab are other linear accelerator-based SRS systems in use as well, but rather than trying to remember all the names, it is helpful to think of them similarly, though some key details are described below. To put it into everyday terms, we can draw an analogy to Coke and Pepsi, two different brands of the same beverage: cola.

Gamma Knife delivers several hundred beams of radiation from a cobalt source. To take you back to high school chemistry, cobalt is one of the elements in the periodic table. The radiation beams concentrate at the point where all the beams meet (see picture). The radiation beams travel through hundreds of holes in the helmet to converge on the tumor, allowing a high dose of radiation to be delivered to the tumor, while sparing the surrounding tissue from the high dose. SRS is highly dependent on accuracy, and requires that the patient's head be securely stabilized using a helmet (head frame), so there is no movement during the treatment. Finally, there is a size limit for Gamma Knife; the metastases should be 3 cm or smaller.

X-knife is a linear accelerator- based treatment. Like Gamma Knife, it requires a head frame which will remain on the patient for the entire procedure, providing a reference for the location of the patient's anatomy.

Cyberknife is a form of frameless SRS using a specialized miniature linear accelerator with a robotic arm. It gets around the issue of using a frame for immobilization by using a custom mask for each patient along with skull-based tracking, allowing the robot to follow a target. Cyberknife can accommodate lesions larger than 3 cm, and can also be used to treat other types of cancer outside the brain.

There have been several studies looking at combining SRS and WBRT (SRS in combination with WBRT vs. WBRT alone). None of these studies has found a significant improvement in survival with the addition of SRS in patients with multiple brain mets. One study, however, found a benefit for the addition of SRS to WBRT in patients with a single metastasis. Patients with a single metastasis who received SRS and WBRT had an average survival of 6.5 months, versus 4.9 months in the group that received WBRT only. This may seem like a small increase, but it tells researchers that the combined therapy may be better than WBRT alone in single brain metastasis. In patients who have had surgery, some physicians may perform SRS to the tumor bed after resection in lieu of post-resection whole brain radiotherapy, and will offer WBRT later, if more metastases develop elsewhere in the brain.

Surgery

For patients with a single brain lesion, surgery may be a good option, given the tumor is under control in the rest of the body, provided the lesion is in an area of the brain where it is safe to operate. A study of patients with a single brain met randomized to WBRT alone vs. surgery followed by WBRT found that patients treated with surgery and WBRT have fewer recurrences, and better quality of life than patients treated with RT alone. Furthermore, time to neurological death was improved from 6 months to 14 months. However, these results do not apply to patients with radiosensitive tumors such as lymphomas, small cell lung cancer, and germ cell tumors (where surgery is generally not recommended). Since SRS can deliver high doses to brain mets with minimal morbidity, you may wonder why open surgery is done at all. One very small randomized trial did compare surgery followed by WBRT to SRS alone and found similar local control and survival for both groups, but because of the small patient numbers, we cannot draw any conclusions. More studies are needed to confirm this finding.

Chemotherapy

It is widely thought that most chemotherapy agents are unable to cross the blood brain barrier; in other words, they move through the blood stream, but cannot enter the brain. This makes the brain a safe haven for cancer cells that "escape" the chemo and make their way there. That being said, researchers have found that brain metastases from tumor types that are particularly sensitive to chemotherapy (testicular, lymphomas, and small cell lung cancer, as previously mentioned) are also sensitive to chemotherapy. In addition, patients that have not already received a lot of chemotherapy may have a greater reduction in brain metastases with chemotherapy treatment. This leads researchers to believe that there is some penetration of the blood brain barrier by chemotherapy, just not always in effective amounts.

One chemotherapy agent, temozolomide (Temodar®), is an oral medication that is capable of crossing the blood-brain barrier, and is used to treat primary brain tumors and metastatic melanoma lesions. The encouraging results in these diseases led to clinical trials in brain metastases. Early trials done in conjunction with WBRT appeared to be promising but did not show a survival advantage. Other chemotherapy agents which have been studied with WBRT included thalidomide, teniposide, topootecan, paclitaxel, and cisplatin, however none has shown enough of a benefit to support the routine use of chemotherapy as treatment of brain metastases.

Investigational Agents: Radiosensitizers

One of the reasons that brain lesions are difficult to treat with radiation is based on the fact that radiation requires oxygen to work. Brain lesions (both primary and metastases) are generally lacking oxygen. Some agents, by increasing the levels of oxygen in the tumor, make it more sensitive to radiation therapy; these agents are known as "radiosensitizers". Two recently-studied agents are motexafin gadolinium (Xcytrin) and Efaproxyn (efaproxiral or RSR-13).

Motexafin gadolinium is thought to have an effect on cell function that leads to cell death, as well as an increase in sensitivity to radiation. Although trials were conducted in several tumor types, it was only found to have significant activity in non small-cell lung cancer (NSCLC). It improved time to progression but did not improve survival and the FDA did not approve the drug. RSR-13, another radiosensitizer was studied in breast cancer patients. Although initial results were promising, with longer follow-up, RSR-13 did not show an improvement in survival. The FDA did not recommend approval of this drug for use in conjunction with whole brain radiation. Overall, the evidence to support use of radiosensitizers in conjunction with WBRT is weak; therefore radiosensitizers are generally not used.

Small cell lung cancer is associated with a very high risk for brain metastases; approximately 50% of patients develop lesions within two years of diagnosis. For this reason, researchers looked at utilizing whole brain radiation as a way to prevent future brain metastases from developing. When whole brain radiation is given as a preventive measure, it is also known by the name "prophylactic cranial irradiation" or "PCI." Studies of PCI have shown significant decreases in brain mets (from 55% to 19% at 2 years and from 56% to 35% at 3 years) and increases in overall survival. Some have suggested there may be long-term neurologic impairment from this treatment, but long-term neurotoxicity data is lacking. PCI is the standard of care for patients with limited-stage small cell lung cancer who have complete remission after local therapy. Studies are ongoing to assess any benefits of this practice in other tumor types.

Conclusions

To summarize, there are multiple approaches to the treatment of brain metastases. For patients with a single lesion, approaches that are supported by randomized clinical trials are resection followed by WBRT, and for unresected lesions, WBRT followed by SRS, or SRS alone. For multiple metastases, there are also a number of options, but WBRT is used more often and surgery less often as compared to patients with a single metastasis; SRS can be used depending on the number and size of lesions, alone or as a "boost" to WBRT. Keep in mind that these are generalizations and each patient should receive individualized care, depending on their unique situation. Treatment decisions also factor in the patient's performance status, how well controlled the primary cancer is, and the patient's goals of care.

Clinical trials of new agents and techniques continue to seek better therapies for patients affected by these tumors. A study currently open (ClinicalTrials.gov number, NCT00377156) involves the randomization of patients with one to three brain metastases to undergo SRS alone or SRS followed by whole-brain radiation therapy.

Use our Cancer Types menu to find more information about primary tumor types and their treatment.

Sep 26, 2011 - Salvage stereotactic radiosurgery is a reasonable treatment for breast cancer brain metastases, with a median overall survival of more than nine months, according to a study published online Sept. 14 in Cancer.